Wounds and wound healing disorders are pervasive and detract from the quality of life. Wounds that sever nerve communication result in paralysis. Wound healing disorders afflict wounds in organs and tissues after traumatic injuries and infection and equally include wounds and wound-like conditions following surgical interventions as is frequently required for vascular diseases arising from progressive disorders such as atherosclerosis. For example, vascular diseases, such as coronary or carotid artery disease, affect millions of individuals in the U.S. and many more worldwide. See, e.g., Ma et al., J. Clin. Exp. Med., 3(3):192-201 (2010). Therapeutic intervention for vascular disease such as blood vessel transplantation, stents and angioplasty can ameliorate the debilitating effects of vascular disease by restoring normal blood flow. The improvements from these interventions may be only temporary, however, since wound healing disorders are commonplace and can give rise to complications such as restenosis, a re-narrowing of vessels following surgical intervention caused by a rapid increase in the number of smooth muscle cells of the vessel wall.
These novel observations relate directly to the debate in the art as to the identity and/or source of cells that give rise to wound healing lesions, such as those associated with blood vessel wound healing disorders such as post-surgical restenosis. Some authors have presented data that an undefined subset of the cells isolated from adventitia of aortic arches have certain stem cell-like properties (such as cell expression of cell surface markers) and a capacity to produce cells that may contribute to atherosclerosis. Hu et al., J. Clin. Invest., 133(9): 1258-65 (2004). These studies of atherosclerosis are distinguished from the events of wound healing, such as post-surgical restenosis, described herein because the slow progression of atherosclerotic plaques over many decades is recapitulated in a matter of weeks and months in post-surgical restenosis. Restenosis has in fact been characterized as “galloping atherosclerosis.” These studies do not establish a clear role for the specific cells studied in a disease state, let alone any morphological characterization of the cells to aid in their identification or classification, e.g., by microscopic examination by medical pathologists or histologists.
Other authors have described the distribution of cells with particular surface antigens and other characteristics, while characterizing the location of cells with possible stem cell like characteristics in vascular and/or vascular-proximate tissues. Unfortunately, it has been demonstrated that such antigenic markers or stem cells are widely distributed on and among cells that are not stem cells. Said markers are useful in enriching stem cells from cell mixtures but do not permit isolation and observation of stem cells specifically. See, Pasquinelli et al., Cytotherapy, 12:275-87 (2010). These studies, however, do not demonstrate a role for the cells with stem-like properties in any disease. In particular, Pasquinelli et al., did not observe symmetric or asymmetric amitoses of metakaryotes in vascular walls and did not observe creation of smooth muscle cells by asymmetric amitoses of metakaryotic cells. Accordingly, there is a need to identify cell types involved in wound healing and wound healing disorders. In addition, there is a need to identify agents to treat wound healing disorders by modulating growth and/or migration of cells involved in wound healing—i.e., stem cells involved in actual disease states. There is a further need for methods to identify agents to treat wound healing disorders characterized by aberrant excess tissue generation—e.g., by killing and/or slowing the migration, increase or production of differentiated cells for stem cells underlying the pathological disorders. This is particularly true for smooth muscle cells in the case of post-surgical restenosis